title: Assessment of the genotoxic potential of azidothymidine in the comet, micronucleus, and Pig-a assay.
abstract: The genotoxic potential of azidothymidine (Zidovudine, AZT), chosen as a model compound for nucleotide analogs, was comprehensively assessed in vivo for gene mutation, clastogenicity, and DNA breakage endpoints. Male Wistar rats were treated by oral gavage over 7 days with AZT at dose levels of 2×0 (control), 2×250, 2×500, and 2×1000mg/kg/day with a final single dose given on day 8. DNA damage was then evaluated with the comet assay in liver, stomach, and peripheral blood and with the micronucleus test in bone marrow and peripheral blood (by flow cytometry) in the same animals. After a treatment-free period of upto 42 days, the Pig-a gene mutation assay was performed in peripheral blood of the high-dose animals. In the comet assay as well as the micronucleus test, AZT caused a considerable dose-dependent increase in DNA damage in all tissues evaluated and was highly cytotoxic to bone marrow and peripheral blood cells. These data are well in line with published results. Surprisingly, AZT did not significantly increase the number of Pig-a mutant cells. We speculate that two factors likely contributed to this negative result: a predominance of large deletions caused by AZT, and the relatively low statistical power of the first-generation scoring method used for this study.
authors.affiliation: * F. Hoffmann-La Roche AG, Non-Clinical Safety, 4070 Basel, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
authors.forename: Julie
authors.initials: J
authors.lastname: Koenig
authors.forename: Matthias
authors.initials: M
authors.lastname: Festag
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dertinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Georg
authors.initials: G
authors.lastname: Schmitt
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeller
mesh_terms: D000818:Animals; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D009153:Mutagens; D015215:Zidovudine
keywords: 3′-azido-3′-deoxythymidine; Pig-a assay; Zidovudine.; azidothymidine; comet assay; micronucleus test; rat